One-third of all individuals in the United States will develop cancer (American Cancer Society Yearly Outlook for 1990). Cancer is second only to cardiac disease as a cause of death in this country (American Cancer Society Yearly Outlook for 1990). Currently, cancer therapy employs a variety of procedures including the administration of chemicals, chemotherapy, radiation, radiotherapy, and surgery.
Radiotherapy is a regional form of treatment used for the control of localized cancers (See Devita, V. T., in Harrison's Principles of Internal Medicine, Braunwald et al., eds., McGraw-Hill Inc., New York, 1987, pp. 431-446). Radiotherapy relies on the fact that some malignant cells are more susceptible to damage by radiation than normal cells. Unfortunately, some tumors cannot be treated with radiotherapy. Moreover, irradiation and radioisotope therapy can induce extensive damage of normal tissues.
Surgery is still considered the primary treatment for most early cancers. Although most tumors are operable, they not fully resectable. Some tumors that appear resectable have micrometastatic disease outside the tumor field. This leads to a recurrence of the cancer close to the initial site of occurrence.
Cancer chemotherapeutic agents, even though widespread in use, have proved to be of limited effect in treating most cancer types. Although there have been some notable successes in the treatment of some specific tumor types (e.g., childhood leukemias) with conventional chemotherapy, more limited success has been obtained in the treatment of solid tumors. This failure is primarily due to the low therapeutic index of many anti-cancer drugs, as well as the intrinsic or acquired drug resistance that often characterizes tumor cells. Another drawback to the use of cytotoxic agents for the treatment of cancer is their severe side effects. These include nausea, vomiting, CNS depression, localized pain, bone marrow depression, bleeding, renal damage, hypo and hyperglycemia, and hypersensitivity reactions. Another drawback is that most anti-cancer drugs are only effective against rapidly dividing cells.
Cancer can be considered as a disturbed balance between the relative rates of cell proliferation and cell death. Until recently, it was thought that the ultimate result of treatment with anti-cancer drugs was cellular necrosis, a form of cell death that involves a swelling of the cells and membrane rupture. Recently, it has been determined that many anti-cancer drugs induce cell death by apoptosis. Apoptotic cell death is an orderly process which is typically accompanied by one or more characteristic morphological and biochemical changes in cells, such as condensation of cytoplasm, loss of plasma membrane microvilli, segmentation of the nucleus, degradation of chromosomal DNA or loss of mitochondrial function. A recognized biochemical marker of apoptosis is the cleavage of chromatin into nucleosomal fragments.
Certain tumor suppressor proteins, such as p53, have been reported to have a role in inducing apoptosis. Apoptosis is also triggered by the activation of a family of cysteine proteases having specificity for aspartic acid residues. These proteases are designated as caspases (Alnemri, et al., Cell, 87:171, (1996)). One identified substrate for caspase-3 is poly (ADP-ribose) polymerase (PARP).
About 50% of human tumors have been shown to have deletions or mutations in the p53 gene and gene product. As a result of this mutation, the cells of these tumors may not be able to undergo apoptosis. This fact may explain the relatively low intrinsic sensitivity of tumors with p53 mutations to conventional chemotherapy.
The need still exists for improved methods for the treatment of most types of cancers. Additional therapeutic methods for inhibiting or reversing the growth of mammalian tumors, particularly human tumors, are desirable. Methods which induce apoptosis of tumor cells or cancer cells, particularly those methods which induce apoptosis of cancer cells in a p53 independent manner, are especially desirable.